Table 6.
Epigenetic effects of exogenous and endogenous molecules and of genetic variants on mtDNA methylation and hydroxymethylation.
| Experimental Model | Method | mtDNA region Investigated | Observation | Reference |
|---|---|---|---|---|
| Effect of valproic acid in mouse 3T3-L1 cells | ELISA and enzymatic restriction digestion | D-loop region and COX3 and MT-ND5 genes. Global 5-mC and 5-hmC mtDNA content. | Decreased 5-hmC at global level, in MT-ND5 and COX3 genes and in D-loop region | [51] |
| Peripheral blood of individuals exposed to particulate matter (PM1), air benzene and traffic-derived elemental carbon exposure | Pyrosequencing | D-loop region, MT-TF and MT-RNR1 genes | MT-TF and MT-RNR1 methylation levels positively correlated with PM1, as well as with mtDNA copy number | [108] |
| Frontal lobe of Wistar rats exposed to the endocrine disruptor polybrominated dyphenil ether BDE-47 | Pyrosequencing, Immunohistochemistry | Mt-co1, Mt-co2 and Mtco3 mitochondrial genes; Bdnf and Nr3c1 nuclear genes. Global nuclear 5-hmC and 5-mC content. | Decreased methylation levels of Mt-co2, Bdnf and Nr3c1 genes, together with decrease in global DNA methylation in rats exposed to BDE-47 | [109] |
| Effect of PM2.5 on human placenta | Pyrosequencing | D-loop region, MT-RNR1 gene | PM2.5 levels positively correlated with both MT-RNR1 and D-loop methylation and inversely correlated with mtDNA content | [56] |
| Maternal betaine supplementation during gestation in pregnant sows | 5mC Immunoprecipitation followed by qPCR | D-loop region and mt-Cox1, mt-Cox3 and mt-Nd4 genes | Decreased D-loop methylation levels and increased expression of mtDNA genes in the muscle of newborn piglets | [110] |
| Liver of large yellow croakers (Larimichthys crocea) fed with different lipid sources (fish oil (FO), palmitic acid, olive oil (OO), sunflower oil or perilla oil (PO)) | Pyrosequencing | D-loop region, MT-TR, MT-ND4L and MT-RNR1 genes | MT-TR and MT-NAD4L methylation higher in the OO and PO than in the FO, whereas MT-RNR1 methylation was lower in the OO group than in the FO group | [111] |
| Effect of maternal smoking during pregnancy in placenta and foreskin | Pyrosequencing | D-loop region | Positive association between D-loop methylation and maternal smoking during pregnancy | [112] |
| Association between exposure to particulate matter (PM2.5) and blood mtDNA methylation in relation to heart rate variability (HRV) markers | Pyrosequencing | D-loop region, MT-TF and MT-RNR1 genes | D-loop methylation negatively associated with PM2.5 levels. Participants with higher mtDNA methylation levels were more susceptible to the effect of PM2.5 on HRV. | [113] |
| Polycystic ovaries (PCO) of gilts with hyperhomocysteinemia | Bisulfite sequencing | D-loop region and MT-RNR1, MT-RNR2 and ND4 genes | mtDNA significantly hypermethylated in all regions analyzed in PCO with respect to healthy ovaries | [114] |
| Liver of large yellow croaker fed with one of three diets characterized by a low (6%), moderate (12%, the control diet) or high (18%) crude lipid content | Pyrosequencing | D-loop region and MT-ND6 and MT-RNR1 genes | D-loop methylation levels higher in the high-lipid than the control group. Increased mtDNA copy number in the high-lipid group. | [115] |
| Liver of rats fed with high levels of fructose and with normal diet (control group) | Enzyme-linked immunosorbent assay | Global 5-mC and 5-hmC mtDNA content | Global hypomethylation of mtDNA in fructose-fed rats as well as higher mtDNA content and transcription of several mtDNA genes | [116] |
| Peripheral blood of chrome plating workers and control subjects | Sequenom MassARRAY platform | MT-TF and MT-RNR1 genes | The mtDNA methylation was lower in chrome-exposed compared to control subjects | [117] |
| Effect of maternal smoking during pregnancy on placenta | Pyrosequencing | D-loop region, and MT-RNR1 gene; nuclear CYP1A1 gene | Higher MT-RNR1 gene methylation levels and lower mtDNA content in placenta samples of smoker pregnant mothers | [118] |
| Effect of cord blood thyroid hormones thyroxine (T4) and triiodothyronine (FT3) on placenta methylation levels | Pyrosequencing | D-loop region, MT-RNR1 gene | MT-RNR1 and D-loop methylation inversely correlated with thyroid hormones levels. Positive association between thyroid hormones and placenta mtDNA content. | [119] |
| Peripheral blood of welders exposed to respirable dust | Pyrosequencing | D-loop region, MT-TF gene | Decreased D-loop and MT-TF methylation and increased mtDNA copy number associated with welding fumes exposure | [120] |
| Hippocampus of rats that received iron in the neonatal period and cannabidiol (CBD) for 14 days in adulthood |
Enzyme-linked immunosorbent assay | Global 5-mC and 5-hmC mtDNA content | Iron induced decreased levels of both 5-mC and 5-hmC. CBD induced increase in 5-hmC but not in 5-mC. | [121] |
| Peripheral blood of individuals exposed to arsenic in drinking water and of control subjects | Methylation-specific PCR | D-loop region and MT-ND6 gene | D-loop and MT-ND6 hypomethylation, increased MT-ND6, MT-ND4 and TFAM gene expression as well as increased mtDNA copy number in individuals exposed to arsenic | [59] |
| Glioblastoma multiforme HSR-GBM1 cell line exposed to the DNA demethylation agents 5-azacytidine and vitamin C | MeDIP-Seq | Multiple mtDNA sequences | Reduced mtDNA methylation at most of the regions analyzed | [122] |
| Association between mtDNA methylation and mitochondrial-derived peptides (MDPs), including HN, MOTS-c and SHLPs in cord blood tissue from newborns exposed to air pollutants during gestation | Pyrosequencing | D-loop, MT-TF and MT-RNR1 genes | Liver tissue from mice exposed for 10 weeks to particulate matter had higher MDP levels. DNA methylation of two distinct regions of the D-Loop was associated with levels of MDPs. | [123] |
| Frozen platelet pellets from 26 women peripheral blood samples (9 controls, 8 l-leucine and 9 l-leucine + l-carnitine) | Pyrosequencing | D-loop region and MT-CO1 gene | l-carnitine supplementation increased D-loop methylation in platelets (+6.63%) | [124] |
| Effect of HIV-1 infection and cocaine, either alone or in combination, on mtDNA methylation in human primary astrocyte | Targeted next-generation bisulfite sequencing, pyrosequencing and ELISA assay | D-loop region, MT-CYTB, MT-RNR1 and MT-ND1 genes. Global mtDNA methylation. | HIV-1 infection and cocaine exposure reduced global methylation and D-loop, MT-RNR1, MT-ND5, MT-ND1 and MT-CYTB genes of mtDNA in vitro and altered the expression of DNMTs and TET proteins both in vitro and in vivo | [125] |
| Porcine oocyte treated with homocysteine | Bisulfite sequencing | MT-RNR1 and MT-RNR2 genes | Increased methylation levels of the MT-RNR2 gene after homocysteine treatment | [126] |
| Peripheral blood mononuclear cells of 20 healthy individuals were isolated from whole blood and stimulated with lipopolysaccharide (LPS) for 48 h | Restriction enzymes followed by qPCR | D-loop region and MT-RNR1 gene and TTF site | Degree of D-loop methylation slightly decreased. Although only modest alterations were seen in the degree of mtDNA methylation, these strongly correlated with IL-6 and IL-10 expression. | [127] |
| Correlations among common polymorphisms of genes required for one-carbon metabolism (MTHFR, MTRR, MTR and RFC-1) and DNA methylation reactions (DNMT1, DNMT3A and DNMT3B) and mtDNA methylation in peripheral blood of 263 subjects | MS-HRM | D-loop region | MTRR 66A > G and DNMT3A −448A > G polymorphisms were significantly associated with D-loop methylation levels | [128] |
| Placental tissue from women who smoked during pregnancy, women with high air pollutant exposure and a control group with low air pollutant exposure | Pyrosequencing | D-loop region; PINK1, DNA2 and POLG1 nuclear genes | D-loop methylation higher in mothers that smoked extensively or highly exposed to air pollutants. D-loop methylation levels inversely correlated with placental mtDNA content and associated with birth weight. | [129] |